ARTHROTEC® CONTAINS DICLOFENAC SODIUM AND
MISOPROSTOL. ADMINISTRATION OF MISOPROSTOL TO WOMEN WHO ARE PREGNANT CAN CAUSE
ABORTION, PREMATURE BIRTH, OR BIRTH DEFECTS. UTERINE RUPTURE HAS BEEN REPORTED
WHEN MISOPROSTOL WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE
ABORTION BEYOND THE EIGHTH WEEK OF PREGNANCY (see also PRECAUTIONS). ARTHROTEC SHOULD NOT BE TAKEN BY
PREGNANT WOMEN (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).

PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE
THE DRUG TO OTHERS. ARTHROTEC should not be used in women of childbearing
potential unless the patient requires nonsteroidal anti-inflammatory drug
(NSAID) therapy and is at high risk of developing gastric or duodenal ulceration
or for developing complications from gastric or duodenal ulcers associated with
the use of the NSAID (see WARNINGS). In such patients, ARTHROTEC may be
prescribed if the patient:

has had a negative serum pregnancy test within 2 weeks prior to beginning
therapy.

is capable of complying with effective contraceptive measures.

has received both oral and written warnings of the hazards of misoprostol,
the risk of possible contraception failure, and the danger to other women of
childbearing potential should the drug be taken by mistake.

will begin ARTHROTEC only on the second or third day of the next normal
menstrual period.

Cardiovascular Risk

NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk may
increase with duration of use. Patients with cardiovascular disease or risk
factors for cardiovascular disease may be at greater risk (see WARNINGS).

ARTHROTEC is contraindicated for treatment of peri-operative pain in the
setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk

NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or intestines,
which can be fatal. These events can occur at any time during use and without
warning symptoms. Elderly patients are at greater risk for serious
gastrointestinal events (see WARNINGS).

Diclofenac sodium is a phenylacetic acid derivative that is a white to
off-white, virtually odorless, crystalline powder. Diclofenac sodium is freely
soluble in methanol, soluble in ethanol and practically insoluble in chloroform
and in dilute acid. Diclofenac sodium is sparingly soluble in water. Its
chemical formula and name are:

CLINICAL PHARMACOLOGY

Pharmacodynamics and pharmacokinetics of diclofenac
sodium

Diclofenac sodium is a nonsteroidal anti-inflammatory drug
(NSAID). In pharmacologic studies, diclofenac sodium has shown
anti-inflammatory, analgesic and antipyretic properties. The mechanism of action
of diclofenac sodium, like other NSAIDs, is not completely understood but may be
related to prostaglandin synthetase inhibition.

Diclofenac sodium is completely absorbed from the GI tract after fasting,
oral administration. The diclofenac sodium in ARTHROTEC is in a pharmaceutical
formulation that resists dissolution in the low pH of gastric fluid but allows a
rapid release of drug in the higher pH environment of the duodenum. Only 50% of
the absorbed dose is systemically available due to first pass metabolism. Peak
plasma levels are achieved in 2 hours (range 1–4 hours), and the area under the
plasma concentration curve (AUC) is dose proportional within the range of 25 mg
to 150 mg. Peak plasma levels are less than dose-proportional and are
approximately 1.5 and 2.0 mcg/mL for 50 mg and 75 mg doses, respectively.

Plasma concentrations of diclofenac sodium decline from peak levels in a
biexponential fashion, with the terminal phase having a half-life of
approximately 2 hours. Clearance and volume of distribution are about 350 mL/min
and 550 mL/kg, respectively. More than 99% of diclofenac sodium is reversibly
bound to human plasma albumin.

Diclofenac sodium is eliminated through metabolism and subsequent urinary and
biliary excretion of the glucuronide and the sulfate conjugates of the
metabolites. Approximately 65% of the dose is excreted in the urine and 35% in
the bile.

Conjugates of unchanged diclofenac account for 5–10% of the dose excreted in
the urine and for less than 5% excreted in the bile. Little or no unchanged
unconjugated drug is excreted. Conjugates of the principal metabolite account
for 20–30% of the dose excreted in the urine and for 10–20% of the dose excreted
in the bile.

Conjugates of three other metabolites together account for 10–20% of the dose
excreted in the urine and for small amounts excreted in the bile. The
elimination half-life values for these metabolites are shorter than those for
the parent drug. Urinary excretion of an additional metabolite (half-life = 80
hours) accounts for only 1.4% of the oral dose. The degree of accumulation of
diclofenac metabolites is unknown. Some of the metabolites may have
activity.

Pharmacodynamics and pharmacokinetics of
misoprostol

Misoprostol is a synthetic prostaglandin E1 analog with gastric antisecretory and (in animals) mucosal
protective properties. NSAIDs inhibit prostaglandin synthesis. A deficiency of
prostaglandins within the gastric and duodenal mucosa may lead to diminishing
bicarbonate and mucus secretion and may contribute to the mucosal damage caused
by NSAIDs.

Misoprostol can increase bicarbonate and mucus production, but in humans this
has been shown at doses 200 mcg and above that are also antisecretory. It is
therefore not possible to tell whether the ability of misoprostol to reduce the
risk of gastric and duodenal ulcers is the result of its antisecretory effect,
its mucosal protective effect, or both.

In vitro studies on canine parietal cells using titrated misoprostol acid as
the ligand have led to the identification and characterization of specific
prostaglandin receptors. Receptor binding is saturable, reversible, and
stereo-specific. The sites have a high affinity for misoprostol, for its acid
metabolite, and for other E type prostaglandins, but not for F or I
prostaglandins and other unrelated compounds, such as histamine or cimetidine.
Receptor-site affinity for misoprostol correlates well with an indirect index of
antisecretory activity. It is likely that these specific receptors allow
misoprostol taken with food to be effective topically, despite the lower serum
concentrations attained.

Misoprostol produces a moderate decrease in pepsin concentration during basal
conditions, but not during histamine stimulation. It has no significant effect
on fasting or postprandial gastrin nor intrinsic factor output.

Effects on gastric acid secretion

Misoprostol, over the range of 50–200 mcg, inhibits basal and
nocturnal gastric acid secretion, and acid secretion in response to a variety of
stimuli, including meals, histamine, pentagastrin, and coffee. Activity is
apparent 30 minutes after oral administration and persists for at least 3 hours.
In general, the effects of 50 mcg were modest and shorter-lived, and only the
200 mcg dose had substantial effects on nocturnal secretion or on histamine- and
meal-stimulated secretion.

Orally administered misoprostol is rapidly and extensively absorbed, and it
undergoes rapid metabolism to its biologically active metabolite, misoprostol
acid. Misoprostol acid in ARTHROTEC reaches a maximum plasma concentration in
about 20 minutes and is, thereafter, quickly eliminated with an elimination
t1/2 of about 30 minutes. There is high variability in
plasma levels of misoprostol acid between and within studies, but mean values
after single doses show a linear relationship with dose of misoprostol over the
range of 200 to 400 mcg. No accumulation of misoprostol acid was found in
multiple-dose studies, and plasma steady state was achieved within 2 days. The
serum protein binding of misoprostol acid is less than 90% and is
concentration-independent in the therapeutic range.

After oral administration of radio-labeled misoprostol, about 70% of detected
radioactivity appears in the urine. Maximum plasma concentrations of misoprostol
acid are diminished when the dose is taken with food, and total availability of
misoprostol acid is reduced by use of concomitant antacid. Clinical trials were
conducted with concomitant antacid; this effect does not appear to be clinically
important.

Pharmacokinetic studies also showed a lack of drug interaction with
antipyrine or propranolol given with misoprostol. Misoprostol given for 1 week
had no effect on the steady state pharmacokinetics of diazepam when the two
drugs were administered 2 hours apart.

Pharmacokinetics of ARTHROTEC

The pharmacokinetics following oral administration of a single
dose (see Table 1) or multiple doses of ARTHROTEC
(diclofenac sodium/misoprostol) to healthy subjects under fasted conditions are
similar to the pharmacokinetics of the two individual components.

The rate and extent of absorption of both diclofenac sodium and misoprostol
acid from ARTHROTEC 50 and ARTHROTEC 75 are similar to those from diclofenac
sodium and misoprostol formulations each administered alone.

A 4-week study, comparing plasma level profiles of diclofenac (50
mg bid) in younger (26–46 years) versus older (66–81 years) adults, did not show
differences between age groups (10 patients per age group). In a multiple-dose
(bid) crossover study of 24 people aged 65 years or older, the misoprostol
contained in ARTHROTEC did not affect the pharmacokinetics of diclofenac
sodium.

Differences in the pharmacokinetics of diclofenac have not been detected in
studies of patients with renal (50 mg intravenously) or hepatic impairment (100
mg oral solution). In patients with renal impairment (N=5, creatinine clearance
3 to 42 mL/min), AUC values and elimination rates were comparable to those in
healthy people. In patients with biopsy-confirmed cirrhosis or chronic active
hepatitis (variably elevated transaminases and mildly elevated bilirubins,
N=10), diclofenac concentrations and urinary elimination values were comparable
to those in healthy people.

Pharmacokinetic studies with misoprostol in patients with varying degrees of
renal impairment showed an approximate doubling of t1/2,
Cmax and AUC compared to healthy people. In people over
64 years of age, the AUC for misoprostol acid is increased.

Misoprostol does not affect the hepatic mixed function oxidase (cytochrome
P-450) enzyme system in animals. In a study of people with mild to moderate
hepatic impairment, mean misoprostol acid AUC and Cmax
showed approximately double the mean values obtained in healthy people. Three
people who had the lowest antipyrine and lowest indocyanine green clearance
values had the highest misoprostol acid AUC and Cmax
values.

CLINICAL STUDIES

Osteoarthritis

Diclofenac sodium, as a single ingredient or in combination with
misoprostol, has been shown to be effective in the management of the signs and
symptoms of osteoarthritis.

Rheumatoid arthritis

Diclofenac sodium, as a single ingredient or in combination with
misoprostol, has been shown to be effective in the management of the signs and
symptoms of rheumatoid arthritis.

Upper gastrointestinal safety

Diclofenac, and other NSAIDs, have caused serious
gastrointestinal toxicity, such as bleeding, ulceration and perforation of the
stomach, small intestine or large intestine. Misoprostol has been shown to
reduce the incidence of endoscopically diagnosed NSAID-induced gastric and
duodenal ulcers. In a 12-week, randomized, double-blind, dose-response study,
misoprostol 200 mcg administered qid, tid or bid, was significantly more
effective than placebo in reducing the incidence of gastric ulcer in OA and RA
patients using a variety of NSAIDs. The tid regimen was therapeutically
equivalent to misoprostol 200 mcg qid with respect to the prevention of gastric
ulcers. Misoprostol 200 mcg given bid was less effective than 200 mcg given tid
or qid. The incidence of NSAID-induced duodenal ulcer was also significantly
reduced with all three regimens of misoprostol compared to placebo (see Table 2).

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of ARTHROTEC
and other treatment options before deciding to use ARTHROTEC. Use the lowest
effective dose for the shortest duration consistent with individual patient
treatment goals (see WARNINGS).

ARTHROTEC is indicated for treatment of the signs and symptoms of
osteoarthritis or rheumatoid arthritis in patients at high risk of developing
NSAID-induced gastric and duodenal ulcers and their complications. See WARNINGS, Gastrointestinal
Effects - Risk of Ulceration, Bleeding and Perforation for a list of
factors that may increase the risk of NSAID-induced gastric and duodenal ulcers
and their complications.

CONTRAINDICATIONS

See boxed CONTRAINDICATIONS AND WARNINGS
related to misoprostol.

ARTHROTEC should not be taken by pregnant women.

ARTHROTEC is contraindicated in patients with hypersensitivity to diclofenac
or to misoprostol or other prostaglandins. ARTHROTEC should not be given to
patients who have experienced asthma, urticaria, or other allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal,
anaphylactic-like reactions to diclofenac sodium have been reported in such
patients (see WARNINGS-
Anaphylactoid Reactions, and PRECAUTIONS- Preexisting Asthma).

ARTHROTEC is contraindicated for the treatment of peri-operative pain in the
setting of coronary artery bypass graft (CABG) surgery (see boxed CONTRAINDICATIONS AND
WARNINGS).

WARNINGS

WARNINGS

Regarding misoprostol:

See boxed CONTRAINDICATIONS AND
WARNINGS.

Regarding diclofenac:

See boxed CONTRAINDICATIONS AND
WARNINGS.

CARDIOVASCULAR EFFECTSCardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective
NSAIDs of up to three years duration have shown an increased risk of serious
cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which
can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a
similar risk. Patients with known CV disease or risk factors for CV disease may
be at greater risk. To minimize the potential risk for an adverse CV event in
patients treated with an NSAID, the lowest effective dose should be used for the
shortest duration possible. Physicians and patients should remain alert for the
development of such events, even in the absence of previous CV symptoms.
Patients should be informed about the signs and/or symptoms of serious CV events
and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the
increased risk of serious CV thrombotic events associated with NSAID use. The
concurrent use of aspirin and an NSAID does increase the risk of serious GI
events (see WARNINGS,
Gastrointestinal Effects - Risk of Ulceration, Bleeding and
Perforation).

Two large, controlled clinical trials of a COX-2 selective NSAID for the
treatment of pain in the first 10–14 days following CABG surgery found an
increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including ARTHROTEC, can lead to onset of new
hypertension or worsening of preexisting hypertension, either of which may
contribute to the increased incidence of CV events. Patients taking thiazides or
loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including ARTHROTEC, should be used with caution in patients with
hypertension. Blood pressure (BP) should be monitored closely during the
initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients
taking NSAIDs. ARTHROTEC should be used with caution in patients with fluid
retention or heart failure.

NSAIDs, including ARTHROTEC, can cause serious gastrointestinal
(GI) adverse events including inflammation, bleeding, ulceration, and
perforation of the stomach, small intestine, or large intestine, which can be
fatal. These serious adverse events can occur at any time, with or without
warning symptoms, in patients treated with NSAIDs. Only one in five patients,
who develop a serious upper GI adverse event on NSAID therapy, is symptomatic.
Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in
approximately 1% of patients treated for 3–6 months, and in about 2–4% of
patients treated for one year. These trends continue with longer duration of
use, increasing the likelihood of developing a serious GI event at some time
during the course of therapy. However, even short-term therapy is not without
risk. NSAIDs should be prescribed with extreme caution in those with a prior
history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for
developing a GI bleed compared to patients treated with neither of these risk
factors. Other factors that increase the risk of GI bleeding in patients treated
with NSAIDs include concomitant use of oral corticosteroids or anticoagulants,
longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
general health status. Most spontaneous reports of fatal GI events are in
elderly or debilitated patients and therefore, special care should be taken in
treating this population.

To minimize the potential risk for an adverse GI event in patients treated
with an NSAID, the lowest effective dose should be used for the shortest
possible duration. Patients and physicians should remain alert for signs and
symptoms of GI ulcerations and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI event is suspected.
This should include discontinuation of the NSAID until a serious GI adverse
event is ruled out. For high risk patients, alternate therapies that do not
involve NSAIDs should be considered.

Renal Effects

Long-term administration of NSAIDs has resulted in renal
papillary necrosis and other renal injury. Renal toxicity has also been seen in
patients in whom renal prostaglandins have a compensatory role in the
maintenance of renal perfusion. In these patients, administration of a
nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in
prostaglandin formation and, secondarily, in renal blood flow, which may
precipitate overt renal decompensation. Patients at greatest risk of this
reaction are those with impaired renal function, heart failure, liver
dysfunction, those taking diuretics and ACE-inhibitors, and the elderly.
Discontinuation of NSAID therapy is usually followed by recovery to the
pretreatment state.

Advanced Renal Disease

ARTHROTEC contains diclofenac. Diclofenac metabolites are
eliminated primarily by the kidneys. The extent to which the metabolites may
accumulate in patients with renal failure has not been studied. Therefore,
treatment with ARTHROTEC is not recommended in these patients with advanced
renal disease. If ARTHROTEC therapy must be initiated, close monitoring of the
patient's renal function is advisable.

Hepatic effects

Elevations of one or more liver tests may occur during therapy
with diclofenac. These laboratory abnormalities may progress, may remain
unchanged, or may be transient with continued therapy. Borderline elevations
(i.e., less than 3 times the ULN [ULN = the upper limit of the normal range]),
or greater elevations of transaminases occurred in about 15% of
diclofenac-treated patients. Of the hepatic enzymes, ALT (SGPT) is the one
recommended for the monitoring of liver injury.

In clinical trials, meaningful elevations (i.e., more than 3 times the ULN)
of AST (SGOT) (ALT was not measured in all studies) occurred in about 2% of
approximately 5,700 patients at some time during diclofenac treatment. In a
large, open, controlled trial, meaningful elevations of ALT and/or AST occurred
in about 4% of 3,700 patients treated for 2–6 months, including marked
elevations (ie, more than 8 times the ULN) in about 1% of the 3,700 patients. In
that open-label study, a higher incidence of borderline (less than 3 times the
ULN), moderate (3–8 times the ULN), and marked (>8 times the ULN) elevations
of ALT or AST was observed in patients receiving diclofenac when compared to
other NSAIDs. Transaminase elevations were seen more frequently in patients with
osteoarthritis than in those with rheumatoid arthritis.

In addition to the borderline elevations of one or more liver tests that may
occur in up to 15% of patients taking NSAIDs including ARTHROTEC, in clinical
trials of diclofenac of up to 3 years in duration, notable elevations of ALT or
AST (approximately three or more times the upper limit of normal) have been
reported in 1–5% of patients including elevations of more than 8 times the ULN.
In addition to enzyme elevations seen in clinical trials, post marketing
surveillance has found rare cases of severe hepatic reactions, including liver
necrosis, jaundice, and fulminant fatal hepatitis with and without jaundice, and
liver failure with rates generally higher than for other NSAIDs. Some of these
reported cases resulted in fatalities or liver transplantation.

Physicians should measure transaminases periodically in patients receiving
long-term therapy with diclofenac, because severe hepatotoxicity may develop
without a prodrome of distinguishing symptoms. The optimum times for making the
first and subsequent transaminase measurements are not known. In the largest
U.S. trial (open-label) that involved 3,700 patients monitored first at 8 weeks
and 1,200 patients monitored again at 24 weeks, almost all meaningful elevations
in transaminases were detected before patients became symptomatic. In 42 of the
51 patients in all trials who developed marked transaminase elevations, abnormal
tests occurred during the first 2 months of therapy with diclofenac. Post
marketing experience has shown severe hepatic reactions can occur at any time
during treatment with diclofenac. Cases of drug-induced hepatotoxicity have been
reported in the first month, and in some cases, the first 2 months of therapy.
Based on these experiences, transaminases should be monitored within 4 to 8
weeks after initiating treatment with diclofenac.

In clinical trials with ARTHROTEC, meaningful elevation of ALT (SGPT, more
than 3 times the ULN) occurred in 1.6% of 2,184 patients treated with ARTHROTEC
and in 1.4% of 1,691 patients treated with diclofenac sodium. These increases
were generally transient, and enzyme levels returned to within the normal range
upon discontinuation of therapy with ARTHROTEC. The misoprostol component of
ARTHROTEC does not appear to exacerbate the hepatic effects caused by the
diclofenac sodium component. A patient with symptoms and/or signs suggesting
liver dysfunction, or in whom an abnormal liver test has occurred, should be
evaluated for evidence of the development of more severe hepatic reaction while
on therapy with ARTHROTEC.

To minimize the possibility that hepatic injury will become severe between
transaminase measurements, physicians should inform patients of the warning
signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus,
jaundice, right upper quadrant tenderness, and "flu-like" symptoms), and the
appropriate action patients should take if these signs and symptoms
appear.

Anaphylactoid reactions

As with other NSAIDs, anaphylactoid reactions may occur in
patients without known prior exposure to ARTHROTEC. ARTHROTEC should not be
given to patients with the aspirin triad. This symptom complex typically occurs
in asthmatic patients who experience rhinitis with or without nasal polyps, or
who exhibit severe, potentially fatal bronchospasm after taking aspirin or other
NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS—Preexisting asthma). Emergency
help should be sought in cases where an anaphylactoid reaction occurs. Allergic
reactions have been reported by less than 0.1% of patients who received
ARTHROTEC in clinical trials, and there have been rare reports of anaphylaxis in
the marketed use of ARTHROTEC outside of the United States.

Skin Reactions

NSAIDs, including ARTHROTEC, can cause serious skin adverse
events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic
epidermal necrolysis (TEN), which can be fatal. These serious events may occur
without warning. Patients should be informed about the signs and symptoms of
serious skin manifestations and use of drug should be discontinued at the first
appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

In late pregnancy, as with other NSAIDs, ARTHROTEC should be
avoided because it may cause premature closure of the ductus arteriosus.

PRECAUTIONS

General

ARTHROTEC cannot be expected to substitute for corticosteroids or
to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids
may lead to disease exacerbation. Patients on prolonged corticosteroid therapy
should have their therapy tapered slowly if a decision is made to discontinue
corticosteroids.

The pharmacological activity of ARTHROTEC in reducing fever and inflammation
may diminish the utility of these diagnostic signs in detecting complications of
presumed noninfectious, painful conditions.

Hepatic Effects

See WARNINGS.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including
ARTHROTEC. This may be due to fluid retention, occult or gross GI blood loss, or
an incompletely described effect upon erythropoiesis. Patients on long-term
treatment with NSAIDs, including ARTHROTEC, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding
time in some patients. Unlike aspirin, their effect on platelet function is
quantitatively less, of shorter duration, and reversible. Patients receiving
ARTHROTEC who may be adversely affected by alterations in platelet function,
such as those with coagulation disorders or patients receiving anticoagulants,
should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use
of aspirin in patients with aspirin-sensitive asthma has been associated with
severe bronchospasm which can be fatal. Since cross reactivity, including
bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has
been reported in such aspirin-sensitive patients, ARTHROTEC should not be
administered to patients with this form of aspirin sensitivity and should be
used with caution in patients with preexisting asthma.

Aseptic meningitis

As with other NSAIDs, aseptic meningitis with fever and coma has
been observed on rare occasions in patients on diclofenac therapy. Although it
is probably more likely to occur in patients with systemic lupus and related
connective tissue diseases, it has been reported in patients who do not have an
underlying chronic disease. If signs or symptoms of meningitis develop in a
patient on diclofenac, the possibility of its being related to diclofenac should
be considered.

Porphyria

The use of ARTHROTEC in patients with hepatic porphyria should be
avoided. To date, one patient has been described in whom diclofenac sodium
probably triggered a clinical attack of porphyria. The postulated mechanism,
demonstrated in rats, for causing such attacks by diclofenac sodium, as well as
some other NSAIDs, is through stimulation of the porphyrin precursor
delta-aminolevulinic acid (ALA).

Information for patients

Women of childbearing potential using ARTHROTEC to treat
arthritis should be told that they must not be pregnant when therapy with
ARTHROTEC is initiated, and that they must use an effective contraception method
while taking ARTHROTEC. See boxed CONTRAINDICATIONS AND
WARNINGS.

THE PATIENT SHOULD NOT GIVE ARTHROTEC TO ANYONE ELSE.
ARTHROTEC has been prescribed for the patient's specific condition, may not be
the correct treatment for another person, and may be dangerous to the other
person if she were to become pregnant.

SPECIAL NOTE FOR WOMEN: ARTHROTEC contains diclofenac sodium
and misoprostol. Misoprostol may cause abortion (sometimes incomplete),
premature labor, or birth defects if given to pregnant women.

Patients should be informed of the following information
before initiating therapy with an NSAID and periodically during the course of
ongoing therapy. Patients should also be encouraged to read the NSAID Medication
Guide that accompanies each prescription dispensed.

ARTHROTEC, like other NSAIDs, may cause serious side effects, such as MI or
stroke, which may result in hospitalization and even death. Although serious CV
events can occur without warning symptoms, patients should be alert for the
signs and symptoms of chest pain, shortness of breath, weakness, slurring of
speech, and should ask for medical advice when observing any indicative sign or
symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, CARDIOVASCULAR
EFFECTS).

ARTHROTEC, like other NSAIDs, can cause GI discomfort and, rarely, serious
GI side effects, such as ulcers and bleeding, which may result in
hospitalizations and even death. Although serious GI tract ulcerations and
bleeding can occur without warning symptoms, patients should be alert for the
signs and symptoms of ulceration and bleeding, and should ask for medical advice
when observing any indicative sign or symptoms, including epigastric pain,
dyspepsia, melena, and hematemesis. Patients should be apprised of the
importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of
Ulceration, Bleeding and Perforation).

ARTHROTEC, like other NSAIDs, can cause serious skin side effects, such as
exfoliative dermatitis, SJS and TEN, which may result in hospitalization and
even death. Although serious skin reactions may occur without warning, patients
should be alert for the signs and symptoms of skin rash and blisters, fever, or
other signs of hypersensitivity such as itching, and should ask for medical
advice when observing any indicative sign or symptoms. Patients should be
advised to stop the drug immediately if they develop any type of rash and
contact their physicians as soon as possible.

Patients should promptly report signs or symptoms of unexplained weight gain
or edema to their physicians.

Patients should be informed of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper
quadrant tenderness and "flu-like" symptoms). If these occur, patients should be
instructed to stop therapy and seek immediate medical attention.

Patients should be informed of the signs of an anaphylactoid reaction (e.g.
difficulty breathing, swelling of the face or throat). If these occur, patients
should be instructed to seek immediate emergency help (see WARNINGS, Anaphylactoid reactions).

In late pregnancy, as with other NSAIDs, ARTHROTEC should be avoided because
it may cause premature closure of the ductus arteriosus.

See PATIENT
INFORMATION at the end of this labeling for important information to
discuss with the patient.

ARTHROTEC is available only as a unit-of-use package that includes a leaflet
containing patient information. The patient should read the leaflet before
taking ARTHROTEC and each time the prescription is renewed because the leaflet
may have been revised. Keep ARTHROTEC out of the reach of children.

Laboratory tests

Because serious GI tract ulcerations and bleeding can occur
without warning symptoms, physicians should monitor for signs of symptoms of GI
bleeding. Patients on long-term treatment with NSAIDs should have their CBC and
a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur
(e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen,
ARTHROTEC should be discontinued.

Effect on blood coagulation

Diclofenac sodium impairs platelet aggregation but does not
affect bleeding time, plasma thrombin clotting time, plasma fibrinogen, or
factors V and VII to XII. Statistically significant changes in prothrombin and
partial thromboplastin times have been reported in normal volunteers. The mean
changes were observed to be less than 1 second in both instances, however, and
are unlikely to be clinically important. Diclofenac sodium is a prostaglandin
synthetase inhibitor, however, and all drugs that inhibit prostaglandin
synthesis interfere with platelet function to some degree; therefore, patients
who may be adversely affected by such an action should be carefully observed.
Misoprostol has not been shown to exacerbate the effects of diclofenac on
platelet activity.

Drug interactionsACE-Inhibitors

Reports suggest that NSAIDs may diminish the antihypertensive
effect of ACE-inhibitors. This interaction should be given consideration in
patients taking NSAIDs concomitantly with ACE-inhibitors.

Aspirin

When ARTHROTEC is administered with aspirin, the protein binding
of diclofenac is reduced, although the clearance of the free ARTHROTEC is not
altered. The clinical significance of this interaction is not known; however, as
with other NSAIDs, concomitant administration of diclofenac sodium and aspirin
is not generally recommended because of the potential risk of increased adverse
effects.

Digoxin

Elevated digoxin levels have been reported in patients receiving
digoxin and diclofenac sodium. Patients receiving digoxin and ARTHROTEC should
be monitored for possible digoxin toxicity.

Warfarin

The effects of warfarin and NSAIDs on GI bleeding are
synergistic, such that users of both drugs together have a risk of serious
bleeding greater than users of either drug alone.

Oral hypoglycemics

Diclofenac sodium does not alter glucose metabolism in healthy
people nor does it alter the effects of oral hypoglycemic agents. There are rare
reports, however, from marketing experience, of changes in effects of insulin or
oral hypoglycemic agents in the presence of diclofenac sodium that necessitated
change in the doses of such agents. Both hypo- and hyperglycemic effects have
been reported. A direct causal relationship has not been established, but
physicians should consider the possibility that diclofenac sodium may alter a
diabetic patient's response to insulin or oral hypoglycemic agents.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate
accumulation in rabbit kidney slices. This may indicate that they could enhance
the toxicity of methotrexate. Caution should be used when NSAIDs are
administered concomitantly with methotrexate.

Cyclosporine

ARTHROTEC, like other NSAID containing products, may affect renal
prostaglandins and increase the toxicity of certain drugs. Ingestion of
ARTHROTEC may increase cyclosporine nephrotoxicity. Patients who begin taking
ARTHROTEC or who increase their dose of ARTHROTEC while taking cyclosporine may
develop toxicity characteristic for clyclosporine. They should be observed
closely, particularly if renal function is impaired.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a
reduction in renal lithium clearance. The mean minimum lithium concentration
increased 15% and the renal clearance was decreased by approximately 20%. These
effects have been attributed to inhibition of renal prostaglandin synthesis by
the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects
should be observed carefully for signs of lithium toxicity.

Antacids

Antacids reduce the bioavailability of misoprostol acid. Antacids
may also delay absorption of diclofenac sodium. Magnesium-containing antacids
exacerbate misoprostol-associated diarrhea. Thus, it is not recommended that
ARTHROTEC be coadministered with magnesium-containing antacids.

Diuretics

Clinical studies, as well as post marketing observations, have
shown that ARTHROTEC can reduce the natriuretic effect of furosemide and
thiazides in some patients. This response has been attributed to inhibition of
renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the
patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as
well as to assure diuretic efficacy. Concomitant therapy with potassium-sparing
diuretics may be associated with increased serum potassium levels.

Other drugs

In small groups of patients (7–10 patients/interaction study),
the concomitant administration of azathioprine, gold, chloroquine,
D-penicillamine, prednisolone, doxycycline or digitoxin did not significantly
affect the peak levels and AUC levels of diclofenac sodium. Phenobarbital
toxicity has been reported to have occurred in a patient on chronic
phenobarbital treatment following the initiation of diclofenac therapy. In
vitro, diclofenac interferes minimally with the protein binding of prednisolone
(10% decrease in binding). Benzylpenicillin, ampicillin, oxacillin,
chlortetracycline, doxycycline, cephalothin, erythromycin, and sulfamethoxazole
have no influence, in vitro, on the protein binding of diclofenac in human
serum.

Animal toxicology

A reversible increase in the number of normal surface gastric
epithelial cells occurred in the dog, rat, and mouse during long-term toxicology
studies with misoprostol. No such increase has been observed in humans
administered misoprostol for up to 1 year. An apparent response of the female
mouse to misoprostol in long-term studies at 100 to 1000 times the human dose
was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not
occur in long-term studies in the dog and rat and has not been seen in humans
treated with misoprostol.

Carcinogenesis, mutagenesis, impairment of
fertility

Long-term animal studies to evaluate the potential for
carcinogenesis and animal studies to evaluate the effects on fertility have been
performed with each component of ARTHROTEC given alone. ARTHROTEC itself
(diclofenac sodium and misoprostol combinations in 250:1 ratio) was not
genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward
mutation test, the rat lymphocyte chromosome aberration test or the mouse
micronucleus test.

In a 24-month rat carcinogenicity study, oral misoprostol at doses up to 2.4
mg/kg/day (14.4 mg/m2/day, 24 times the recommended
maximum human dose of 0.6 mg/m2/day) was not tumorigenic.
In a 21-month mouse carcinogenicity study, oral misoprostol at doses up to 16
mg/kg/day (48 mg/m2/day), 80 times the recommended
maximum human dose based on body surface area, was not tumorigenic. Misoprostol,
when administered to male and female breeding rats in an oral dose range of 0.1
to 10 mg/kg/day (0.6 to 60 mg/m2/day, 1 to 100 times the
recommended maximum human dose based on body surface area) produced dose-related
pre- and post-implantation losses and a significant decrease in the number of
live pups born at the highest dose. These findings suggest the possibility of a
general adverse effect on fertility in males and females.

In a 24-month rat carcinogenicity study, oral diclofenac sodium up to 2
mg/kg/day (12 mg/m2/day) was not tumorigenic. For a 50-kg
person of average height (1.46m2 body surface area), this
dose represents 0.08 times the recommended maximum human dose (148 mg/m2) on a body surface area basis. In a 24-month mouse
carcinogenicity study, oral diclofenac sodium at doses up to 0.3 mg/kg/day (0.9
mg/m2/day, 0.006 times the recommended maximum human dose
based on body surface area) in males and 1 mg/kg/day (3 mg/m2/day, 0.02 times the recommended maximum human dose based on
body surface area) in females was not tumorigenic. Diclofenac sodium at oral
doses up to 4 mg/kg/day (24 mg/m2/day, 0.16 times the
recommended maximum human dose based on body surface area) was found to have no
effect on fertility and reproductive performance of male and female rats.

See boxed CONTRAINDICATIONS AND
WARNINGS. Misoprostol may endanger pregnancy (may cause abortion) and
thereby cause harm to the fetus when administered to a pregnant woman.
Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of
the products of conception. Misoprostol has been used to ripen the cervix, to
induce labor, and to treat postpartum hemorrhage, outside of its approved
indication. A major adverse effect of these uses is hyperstimulation of the
uterus. Uterine rupture, amniotic fluid embolism, severe genital bleeding,
shock, fetal bradycardia, and fetal and material death have been reported.
Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk
of complications from uterine hyperstimulation. ARTHROTEC, which contains 200
mcg of misoprostol, is likely to have a greater risk of uterine hyperstimulation
than the 100 mcg tablet of misoprostol. Abortions caused by misoprostol may be
incomplete. If a woman is or becomes pregnant while taking this drug, the drug
should be discontinued and the patient apprised of the potential hazard to the
fetus.

Cases of amniotic fluid embolism, which resulted in maternal and fetal death,
have been reported with use of misoprostol during pregnancy. Severe vaginal
bleeding, retained placenta, shock, fetal bradycardia, and pelvic pain have also
been reported. These women were administered misoprostol vaginally and/or orally
over a range of doses.

Additionally, because of the known effects of nonsteroidal anti-inflammatory
drugs including the diclofenac sodium component of ARTHROTEC, on the fetal
cardiovascular system (closure of ductus arteriosus), use during pregnancy
(particularly late pregnancy) should be avoided.

Teratogenic effects

See boxed CONTRAINDICATIONS and
WARNINGS. Congenital anomalies sometimes associated with fetal death
have been reported subsequent to the unsuccessful use of misoprostol as an
abortifacient, but the drug's teratogenic mechanism has not been demonstrated.
Several reports in the literature associate the use of misoprostol during the
first trimester of pregnancy with skull defects, cranial nerve palsies, facial
malformations, and limb defects.

An oral teratology study has been performed in pregnant rabbits at dose
combinations (250:1 ratio) up to 10 mg/kg/day diclofenac sodium (120 mg/m2/day, 0.8 times the recommended maximum human dose based on
body surface area) and 0.04 mg/kg/day misoprostol (0.48 mg/m2/day, 0.8 times the recommended maximum human dose based on
body surface area) and has revealed no evidence of teratogenic potential for
ARTHROTEC.

Oral teratology studies have been performed in pregnant rats at doses up to
1.6 mg/kg/day (9.6 mg/m2/day, 16 times the recommended
maximum human dose based on body surface area) and pregnant rabbits at doses up
to 1.0 mg/kg/day (12 mg/m2/day, 20 times the recommended
maximum human dose based on body surface area) and have revealed no evidence of
teratogenic potential for misoprostol.

Oral teratology studies have been performed in pregnant mice at doses up to
20 mg/kg/day (60 mg/m2/day, 0.4 times the recommended
maximum human dose based on body surface area), pregnant rats at doses up to 10
mg/kg/day (60 mg/m2/day, 0.4 times the recommended
maximum human dose based on body surface area) and pregnant rabbits at doses up
to 10 mg/kg/day (120 mg/m2/day, 0.8 times the recommended
maximum human dose based on body surface area) and have revealed no evidence of
teratogenic potential for diclofenac sodium.

However, animal reproduction studies are not always predictive of human
response. There are no adequate and well-controlled studies in pregnant
women.

Nursing mothers

Diclofenac sodium has been found in the milk of nursing mothers.
Misoprostol is rapidly metabolised in the mother to misoprostol acid, which is
biologically active and is excreted in breast milk. ARTHROTEC should not be
administered to nursing mothers because the excretion of misoprostol acid could
cause undesirable effects such as diarrhea in nursing infants.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit
prostaglandin synthesis, an increased incidence of dystocia, delayed
parturition, and decreased pup survival occurred.

Pediatric use

Safety and effectiveness of ARTHROTEC in pediatric patients have
not been established.

Geriatric use

As with any NSAIDs, caution should be exercised in treating the
elderly (65 years and older).

Of the more than 2,100 subjects in clinical studies with ARTHROTEC, 25% were
65 and over, while 6% were 75 and over. In studies with diclofenac, 31% of
subjects were 65 and over. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out.

Diclofenac is known to be substantially excreted by the kidney, and the risk
of toxic reactions to ARTHROTEC may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection, and it may be useful to
monitor renal function (see WARNINGS—Renal effects).

Based on studies in the elderly, no adjustment of the dose of ARTHROTEC is
necessary in the elderly for pharmacokinetic reasons (see Pharmacokinetics of ARTHROTEC—Special
populations), although many elderly may need to receive a reduced
dose because of low body weight or disorders associated with aging.

ADVERSE REACTIONS

Adverse reactions associated with ARTHROTEC

Adverse reaction information for ARTHROTEC is derived from Phase
III multinational controlled clinical trials in over 2,000 patients, receiving
ARTHROTEC 50 or ARTHROTEC 75, as well as from blinded, controlled trials of
Voltaren® Delayed-Release Tablets (diclofenac) and
Cytotec® Tablets (misoprostol).

Gastrointestinal

GI disorders had the highest reported incidence of adverse events
for patients receiving ARTHROTEC. These events were generally minor, but led to
discontinuation of therapy in 9% of patients on ARTHROTEC and 5% of patients on
diclofenac. For GI ulcer rates, see CLINICAL STUDIES—Upper gastrointestinal
safety.

GI disorder

ARTHROTEC

Diclofenac

Abdominal pain

21%

15%

Diarrhea

19%

11%

Dyspepsia

14%

11%

Nausea

11%

6%

Flatulence

9%

4%

ARTHROTEC can cause more abdominal pain, diarrhea and other GI symptoms than
diclofenac alone.

Diarrhea and abdominal pain developed early in the course of therapy, and
were usually self-limited (resolved after 2 to 7 days). Rare instances of
profound diarrhea leading to severe dehydration have been reported in patients
receiving misoprostol. Patients with an underlying condition such as
inflammatory bowel disease, or those in whom dehydration, were it to occur,
would be dangerous, should be monitored carefully if ARTHROTEC is prescribed.
The incidence of diarrhea can be minimized by administering ARTHROTEC with food
and by avoiding coadministration with magnesium-containing antacids.

Gynecological

Gynecological disorders previously reported with misoprostol use
have also been reported for women receiving ARTHROTEC (see below).
Postmenopausal vaginal bleeding may be related to administration of ARTHROTEC.
If it occurs, diagnostic workup should be undertaken to rule out gynecological
pathology (see boxed CONTRAINDICATIONS AND
WARNINGS).

Elderly

Overall, there were no significant differences in the safety
profile of ARTHROTEC in over 500 patients 65 years of age or older compared with
younger patients.

Other adverse experiences reported occasionally or rarely with ARTHROTEC,
diclofenac or other NSAIDs, or misoprostol are:

OVERDOSAGE

The toxic dose of ARTHROTEC has not been determined. However,
signs of overdosage from the components of the product have been
described.

Diclofenac sodium

Clinical signs that may suggest diclofenac sodium overdose
include GI complaints, confusion, drowsiness or general hypotonia. Reports of
overdosage with diclofenac cover 66 cases. In approximately one-half of these
reports of overdosage, concomitant medications were also taken. The highest dose
of diclofenac was 5.0 g in a 17-year-old man who suffered loss of consciousness,
increased intracranial pressure, and aspiration pneumonitis, and died 2 days
after overdose. A 24-year-old woman who took 4.0 g and the 28- and 42-year-old
women, each of whom took 3.75 g, did not develop any clinically significant
signs or symptoms. However, there was a report of a 17-year-old female who
experienced vomiting and drowsiness after an overdose of 2.37 g of
diclofenac.

Animal studies show a wide range of susceptibilities to acute overdosage,
with primates being more resistant to acute toxicity than rodents (LD50 in mg/kg: rats, 55; dogs, 500; monkeys, 3200).

Misoprostol

The toxic dose of misoprostol in humans has not been determined.
Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms
of GI discomfort being reported. In animals, the acute toxic effects are
diarrhea, GI lesions, focal cardiac necrosis, hepatic necrosis, renal tubular
necrosis, testicular atrophy, respiratory difficulties, and depression of the
central nervous system. Clinical signs that may indicate an overdose are
sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever,
palpitations, hypotension, or bradycardia.

ARTHROTEC

Symptoms of overdosage with ARTHROTEC should be treated with
supportive therapy. In case of acute overdosage, gastric lavage is recommended.
Induced diuresis may be beneficial because diclofenac sodium and misoprostol
metabolites are excreted in the urine. The effect of dialysis or hemoperfusion
on the elimination of diclofenac sodium (99% protein bound) and misoprostol acid
remains unproven. The use of oral activated charcoal may help to reduce the
absorption of diclofenac sodium and misoprostol.

DOSAGE AND ADMINISTRATION

Carefully consider the potential benefits and risks of ARTHROTEC
and other treatment options before deciding to use ARTHROTEC. Use the lowest
effective dose for the shortest duration consistent with individual patient
treatment goals (see WARNINGS).

After observing the response to initial therapy with ARTHROTEC, the dose and
frequency should be adjusted to suit an individual patient's needs.

For the relief of rheumatoid arthritis and osteoarthritis the recommended
dose is given below.

The recommended dosage for maximal GI mucosal protection is
ARTHROTEC 50 tid. For patients who experience intolerance, ARTHROTEC 75 bid or
ARTHROTEC 50 bid can be used, but are less effective in preventing ulcers. This
fixed combination product, ARTHROTEC, is not appropriate for patients who would
not receive the appropriate dose of both ingredients. Doses of the components
delivered with these regimens are as follows:

OA regimen

Diclofenac sodium(mg/day)

Misoprostol(mcg/day)

ARTHROTEC 50

tid

150

600

bid

100

400

ARTHROTEC 75

bid

150

400

Rheumatoid Arthritis

The recommended dosage is ARTHROTEC 50 tid or qid. For patients
who experience intolerance, ARTHROTEC 75 bid or ARTHROTEC 50 bid can be used,
but are less effective in preventing ulcers. This fixed combination product,
ARTHROTEC, is not appropriate for patients who would not receive the appropriate
dose of both ingredients. Doses of the components delivered with these regimens
are as follows:

RAregimen

Diclofenac sodium(mg/day)

Misoprostol(mcg/day)

ARTHROTEC 50

qid

200

800

tid

150

600

bid

100

400

ARTHROTEC 75

bid

150

400

SPECIAL DOSING CONSIDERATIONS

ARTHROTEC contains misoprostol, which provides protection against
gastric and duodenal ulcers (see CLINICAL STUDIES). For gastric ulcer
prevention, the 200 mcg qid and tid regimens are therapeutically equivalent, but
more protective than the bid regimen. For duodenal ulcer prevention, the qid
regimen is more protective than the tid or bid regimens. However, the qid
regimen is less well tolerated than the tid regimen because of usually
self-limited diarrhea related to the misoprostol dose (see ADVERSE REACTIONS—Gastrointestinal), and the
bid regimen may be better tolerated than tid in some patients.

Dosages may be individualized using the separate products (misoprostol and
diclofenac), after which the patient may be changed to the appropriate dose of
ARTHROTEC. If clinically indicated, misoprostol co-therapy with ARTHROTEC, or
use of the individual components to optimize the misoprostol dose and/or
frequency of administration, may be appropriate. The total dose of misoprostol
should not exceed 800 mcg/day, and no more than 200 mcg of misoprostol should be
administered at any one time. Doses of diclofenac higher than 150 mg/day in
osteoarthritis or higher than 225 mg/day in rheumatoid arthritis are not
recommended.

For additional information, it may be helpful to refer to the package inserts
for Cytotec® tablets and Voltaren®
tablets.

HOW SUPPLIED

ARTHROTEC (diclofenac sodium/misoprostol) is supplied as a
film-coated tablet in dosage strengths of either 50 mg diclofenac sodium/200 mcg
misoprostol or 75 mg diclofenac sodium/200 mcg misoprostol. The 50 mg/200 mcg
dosage strength is a round, biconvex, white to off-white tablet imprinted with
four "A's" encircling a "50" in the middle on one side and "SEARLE" and "1411"
on the other. The 75 mg/200 mcg dosage strength is a round, biconvex, white to
off-white tablet imprinted with four "A's" encircling a "75" in the middle on
one side and "SEARLE" and "1421" on the other.

The dosage strengths are supplied in:

Strength

NDC Number

Size

50/200

54868-4164-1

bottle of 30

54868-4164-0

bottle of 60

75/200

54868-4165-1

bottle of 30

54868-4165-0

bottle of 60

Store at or below 25°C (77°F), in a dry area.

PATIENT INFORMATION

Read this leaflet before taking ARTHROTEC (diclofenac sodium 50
or 75 mg/misoprostol 200 mcg) and each time your prescription is renewed,
because the leaflet may be changed.

ARTHROTEC is being prescribed by your doctor for treatment of your arthritis
symptoms while at the same time providing protection from the development of
stomach and intestinal ulcers due to the arthritis medication. ARTHROTEC
contains diclofenac, an arthritis medication. ARTHROTEC also contains
misoprostol to decrease the chance of getting stomach and intestinal ulcers that
sometimes develop with NSAID medications. Serious side effects are still
possible, however, and you should report to your doctor any signs or symptoms of
gastrointestinal ulceration or bleeding, skin rash, weight gain or swelling. If
signs of liver toxicity occur (nausea, fatigue, lethargy, itching, jaundice,
right upper quadrant tenderness, and "flu-like" symptoms) you should stop
therapy and seek immediate medical attention.

If signs of an anaphylactoid reaction occur (e.g. difficulty breathing,
swelling of the face or throat) you should stop therapy and seek immediate
medical attention (see WARNINGS).

Do not take ARTHROTEC if you are pregnant (see boxed CONTRAINDICATIONS AND
WARNINGS). ARTHROTEC contains diclofenac sodium and misoprostol.
Misoprostol can cause abortion (sometimes incomplete which could lead to
dangerous bleeding and require hospitalization and surgery), premature birth, or
birth defects. It is also important to avoid pregnancy while taking this
medication and for at least one month or through one menstrual cycle after you
stop taking it. Misoprostol has been reported to cause the uterus to rupture
(tear) when given after the eighth week of pregnancy. Rupture (tearing) of the
uterus can result in severe bleeding, hysterectomy, and/or maternal or fetal
death.

If you become pregnant during therapy with ARTHROTEC, stop taking ARTHROTEC
and contact your doctor immediately. Remember that even if you are using a means
of birth control, it is still possible to become pregnant. Should this occur,
stop taking ARTHROTEC and consult your doctor immediately.

ARTHROTEC is not recommended for nursing mothers.

ARTHROTEC, like other NSAIDs, may cause an increased risk of heart attack, or
stroke, which can lead to death. This risk may increase with duration of use. If
you have heart disease or risk factors for heart disease, you may be at greater
risk (see boxed CONTRAINDICATIONS AND
WARNINGS). ARTHROTEC should never be used for treatment of
peri-operative pain in the setting of coronary artery bypass graft (CABG)
surgery (see boxed CONTRAINDICATIONS AND
WARNINGS).

Although serious CV events can occur without warning symptoms, ask for
medical advice when observing signs and symptoms of chest pain, shortness of
breath, weakness, or slurring of speech (see boxed CONTRAINDICATIONS AND
WARNINGS).

ARTHROTEC, like other NSAIDs, may cause GI discomfort and, rarely, serious GI
effects such as ulcers and bleeding, which may result in hospitalizations and
even death.

ARTHROTEC may cause diarrhea, abdominal pain, upset stomach and/or nausea in
some people. In most cases these problems develop during the first few weeks of
therapy and stop after about a week with continued treatment. You can minimize
possible diarrhea by making sure you take ARTHROTEC with meals and by avoiding
the use of antacids containing magnesium (if needed, use one containing aluminum
or calcium instead). ARTHROTEC tablets should be swallowed whole, and not
chewed, crushed or dissolved.

Because these side effects are usually mild to moderate and usually go away
in a matter of days, most patients can continue to take ARTHROTEC. If you have
prolonged difficulty (more than 7 days), or if you have severe diarrhea,
cramping and/or nausea, call your doctor.

ARTHROTEC may also cause serious gastrointestinal (GI) adverse events
including inflammation, bleeding, ulceration, and perforation of the stomach,
small intestine, or large intestine, which can lead to death. These events can
occur at any time during use and without warning symptoms. Elderly patients are
at greater risk for serious gastrointestinal events (see boxed CONTRAINDICATIONS AND
WARNINGS). This risk may increase with duration of use.

Although serious GI tract ulcerations and bleeding can occur without warning
symptoms, ask for medical advice when observing signs and symptoms of ulceration
and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis.

(See boxed CONTRAINDICATIONS AND
WARNINGS.)

ARTHROTEC, like other NSAIDs, may cause serious skin side effects,
exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal
necrolysis, which may result in hospitalization and even death.

Although serious skin reactions may occur without warning, ask for medical
advice when observing sign or symptoms, such as skin rash and blisters, fever,
or other signs of hypersensitivity such as itching. Stop the drug immediately at
the first appearance of skin rash or any other signs of hypersensitivity and
contact your physician as soon as possible.

Take ARTHROTEC only according to the directions given by your doctor. Changes
in dose should be made only with your doctor's approval.

Do not give ARTHROTEC to anyone else. It has been prescribed for your
specific condition, may not be the correct treatment for another person, and
could be dangerous for another person, especially a woman who may be, or could
become, pregnant.

This information sheet does not cover all possible side effects of ARTHROTEC.
See your doctor if you have questions.

Keep out of reach of children.

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

See the end of this Medication Guide for a list of prescription NSAID
medicines.)

What is the most important information I should know about
medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart
attack or stroke that can lead to death. This chance increases:

with longer use of NSAID medicines

in people who have heart disease

NSAID medicines should never be used right before or
after a heart surgery called a "coronary artery bypass graft (CABG)."

NSAID medicines can cause ulcers and bleeding in the
stomach and intestines at any time during treatment. Ulcers and bleeding:

can happen without warning symptoms

may cause death

The chance of a person getting an ulcer or bleeding
increases with:

taking medicines called "corticosteroids" and "anticoagulants"

longer use

smoking

drinking alcohol

older age

having poor health

NSAID medicines should only be used:

exactly as prescribed

at the lowest dose possible for your treatment

for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat
(inflammation) from medical conditions such as:

different types of arthritis

menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug
(NSAID)?

Do not take an NSAID medicine:

if you had an asthma attack, hives, or other allergic reaction with aspirin
or any other NSAID medicine

for pain right before or after heart bypass surgery

Tell your healthcare provider:

about all of your medical conditions.

about all of the medicines you take. NSAIDs and some other medicines can
interact with each other and cause serious side effects. Keep a
list of your medicines to show to your healthcare provider and
pharmacist.

if you are pregnant. NSAID medicines should not be used by
pregnant women late in their pregnancy.

if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal
Anti-Inflammatory Drugs (NSAIDs)?

Serious side effects include:

heart attack

stroke

high blood pressure

heart failure from body swelling (fluid retention)

kidney problems including kidney failure

bleeding and ulcers in the stomach and intestine

low red blood cells (anemia)

life-threatening skin reactions

life-threatening allergic reactions

liver problems including liver failure

asthma attacks in people who have asthma

Other side effects include:

stomach pain

constipation

diarrhea

gas

heartburn

nausea

vomiting

dizziness

Get emergency help right away if you have any of the
following symptoms:

shortness of breath or trouble breathing

chest pain

weakness in one part or side of your body

slurred speech

swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider
right away if you have any of the following symptoms:

nausea

more tired or weaker than usual

itching

your skin or eyes look yellow

stomach pain

flu-like symptoms

vomit blood

there is blood in your bowel movement or it is black and sticky like tar

skin rash or blisters with fever

unusual weight gain

swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your
healthcare provider or pharmacist for more information about NSAID
medicines.

Aspirin is an NSAID medicine but it does not increase the chance of a heart
attack. Aspirin can cause bleeding in the brain, stomach, and intestines.
Aspirin can also cause ulcers in the stomach and intestines.

Some of these NSAID medicines are sold in lower doses without a prescription
(over –the –counter). Talk to your healthcare provider before using over –the
–counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

This Medication Guide has been approved by theU.S. Food
and Drug Administration.